The present invention relates to the treatment of ocular disorders of the eye and more particularly to the treatment of glaucoma.
I. Description And Characterization Of Glaucoma
Glaucoma is an ophthalmologic disorder responsible for visual impairment. It is the fourth most common cause of blindness and the second most common cause of visual loss in the United States, and the most common cause of irreversible visual loss among African-Americans. Generally speaking, the disease is characterized by a progressive neuropathy caused at least in part by deleterious effects resulting from increased intraocular pressure on the optic nerve. In normal individuals, intraocular pressures range from 12 to 20 mm Hg., averaging approximately 16 mm Hg. However, in individuals suffering from glaucoma, intraocular pressures generally rise above 25 to 30 mm Hg. and can sometimes reach 70 mm Hg. Importantly, the loss of vision can result from intraocular pressures only slightly above or even within the statistically normal range, in eyes which are unusually pressure-sensitive, over a period of years. Moreover, extremely high pressures (e.g., 70 mm Hg.) may cause blindness within only a few days (See e.g., Kaufman and Mittag, xe2x80x9cMedical Therapy Of Glaucoma,xe2x80x9d in Kaufman and Mittag (eds.), Glaucoma (Vol. 7 of Podos and Yanoff (eds), Textbook of Ophthalmology Series). London, Mosby-Year Book Europe Ltd. [1994], pp. 9.7-9.30; and Guyton, Textbook of Medical Physiology, 6th ed. (W. B. Saunders Co.), pp. 386-89[1981]).
Several different types of glaucomas exist, each having different pathophysiologies and risk factors. In terms of classification, glaucomas may first be deemed to be either xe2x80x9cprimaryxe2x80x9d or xe2x80x9csecondary.xe2x80x9d Primary glaucomas, discussed further below, result directly from anatomical and/or physiological disturbances in the flow of aqueous humor (i.e., intraocular fluid). Secondary glaucomas occur as a sequel to ocular injury (e.g., trauma inflicted to the eye) or preexisting disease (e.g., an intraocular tumor or an enlarged cataract). Though the various secondary glaucomas have different etiologies, they are similar to the primary glaucomas in that they all produce visual loss through optic neuropathy.
The major types of primary glaucomas include (i) open-angle glaucoma (also known as chronic or simple glaucoma), (ii) angle-closure glaucoma (also known as closed-angle or narrow-angle glaucoma), and (iii) congenital glaucoma (also known as infantile glaucoma).
Open-angle glaucoma constitutes approximately 90% of all primary glaucomas. Open angle glaucoma is characterized by abnormally high resistance to fluid drainage from the eye. Intraocular pressure rises to the level required to drive the fluid normally produced by the eye, whose rate of formation is not altered in glaucoma, across the elevated resistance, according to the normal laws of physics governing passive bulk fluid flow across a resistance and down a pressure gradient. Normal resistance is required to maintain an intraocular pressure sufficient to: (i) maintain the shape of the eye (i.e., to keep it inflated) for optical integrity, and (ii) provide a pressure gradient to allow for the flow of aqueous humor, a fluid produced by the eye which provides for the metabolic needs of the avascular cornea and lens. This resistance is provided by the trabecular meshwork (TM), a complex tissue consisting of specialized endothelial cells, connective tissue beams, and extracellular matrix.
Angle-closure glaucoma entails closure or blockage of the anterior chamber angle by another ocular structure (usually the iris), thereby restricting outflow of aqueous humor. Though angle-closure glaucoma only constitutes approximately 5% of primary glaucomas, it requires immediate medical attention (See e.g., Kaufman and Mittag, xe2x80x9cMedical Therapy Of Glaucoma,xe2x80x9d supra).
II. Etiology of Glaucoma
Glaucoma has been associated with both pharmacological and non-pharmacological factors. Non-pharmacological factors include age, race, family history, diabetes, and blood pressure. For example, African Americans are four-to-five times as likely to develop open-angle glaucoma as are Caucasians. Similarly, open-angle glaucoma is much more prevalent in individuals over the age of 40, and especially in those over 60 years of age.
In addition, particular drugs have been associated with glaucoma. The corticosteroids (e.g., prednisone, dexamethasone, and hydrocortisone) are known to induce glaucoma following both ophthalmic and systemic administration by increasing resistance to aqueous humor outflow through the trabecular meshwork via a mechanism somehow genetically linked to primary open angle glaucoma. Dexamethasone has been associated with the most pronounced increase in intraocular pressure, and ophthalmic administration generally leads to greater increases than systemic administration.
Topically applied ophthalmic drugs which dilate the pupil (adrenergic agonists such as phenylephrine and epinephrine; anticholinergics such as atropine, scopolamine, homatropine, cyclopentolate and tropicamide) may induce angle-closure glaucoma, while the anticholinergics can increase resistance to aqueous humor outflow in susceptible individuals even without causing angle-closure, apparently related to their cycloplegic (ciliary muscle/accommodation-paralyzing) action. Adrenergic (e.g., central nervous system stimulants, appetite suppressants) and anticholinergic (e.g., bowel relaxants and tricyclic antidepressants) agents administered systemically may also induce angle closure glaucoma, via secondarily dilating the pupil.
III. Therapeutic Modalities
Current glaucoma therapies are restricted to reducing intraocular pressure. Presently, both surgical and pharmacological treatments are used.
A. Surgical Treatment
Both laser and incisional surgical procedures are employed. Although open-angle glaucoma is generally controlled by pharmacological agents, laser trabeculoplasty or filtering surgery to improve aqueous drainage can be considered in severe cases (See e.g., The Merck Manual of Diagnosis and Therapy (16th Edition, 1992); Sec. 17: Ophthalmologic Disorders; Subsec. 227: Glaucoma; and Wilensky and Jampol, xe2x80x9cLaser therapy for open angle glaucoma,xe2x80x9d Ophthalmol., 88:203-212[1981]).
Because it constitutes a medical emergency, angle-closure glaucoma is the type of glaucoma that most frequently requires surgical intervention. As noted above, angle-closure glaucoma entails closure or blockage of the anterior chamber angle, thereby restricting outflow of aqueous humor. Angle-closure glaucoma can often be permanently cured by laser peripheral iridectomy performed within 12-48 hours after the onset of symptoms (Current Surgical Diagnosis and Treatment, 8th ed., Appleton and Lange, pp. 819-820[1988]). Though often necessary and quite effective for both open- and closed-angle glaucoma, surgical intervention is an invasive form of treatment, even if local anesthesia can be used.
B. Pharmacological Treatment
Chronic open-angle glaucoma is generally treated by ocular administration of one of several agents. For a particular patient, the concentration of the agent and the frequency of administration is generally determined by trial and error, beginning with one of the weaker available preparations (e.g., pilocarpine 1%). The miotic agents (i.e., agents that causes the pupil to contract) represent one frequently used class of glaucoma drugs. Though the precise mechanism of action has not yet been fully elucidated, the miotic drugs lower intraocular pressure in patients suffering from open angle glaucoma by facilitating aqueous humor outflow, in turn consequent to mechanical deformation of the trabecular meshwork by drug-induced contraction of the ciliary muscle. The miotics, appropriately referred to as cyclotonics in this context, may be either direct-acting (e.g., pilocarpine and carbachol, which act on the muscarinic receptors of the ciliary muscle to produce contraction) or indirect-acting (e.g., anti-cholinesterases, such as echothiophate and isoflurophate, which prevent the degradation of the endogenous cholinergic neurotransmitter acetylcholine, thereby permitting strong and continuous contraction of the ciliary muscle). The adverse effects associated with the miotic agents include painful ciliary or accommodative spasm and consequent induced fluctuating myopia and blurred vision (in patients under the age of approximately 45 years), ciliary or conjunctival congestion, ocular pain, headache, and the miosis itself, which can cause a disabling reduction of vision in elderly patients with early cataract formation (the combination of the small pupil and the cloudy lens critically reduce the amount of light reaching the retina). The long-acting anticholinesterases are associated with the most severe and prolonged adverse effects, which may include development of cataracts or retinal detachment.
Several mydriatic agents are also useful in the initial treatment of open-angle glaucoma. For example, the sympathomimetic amines epinephrine and dipivefrin (a synthetic prodrug of epinephrine) lower intraocular pressure, at least in part through stimulation of xcex22-adrenergic receptors in the trabecular meshwork (the mydriatic effect being irrelevant to the reduction in intraocular pressure). The adverse ocular effects of both agents include ocular congestion or hyperemia, ocular pain and headache, and blurred vision. In addition, epinephrine occasionally causes untoward systemic effects, such as palpitation, tachycardia, and hypertension.
In addition, the relatively new xcex12-adrenergic agonist apraclonidine has been shown to be effective in the treatment of glaucoma by inhibition of aqueous humor formation. As with many of the other topical anti-glaucoma preparations, apraclonidine is associated with both ocular (e.g., mydriasis and eyelid retraction) and systemic (e.g., dry mouth and nose) adverse effects.
Both non-selective xcex21- and xcex22-adrenergic blocking agents (e.g., timolol and levobunolol) and xcex21-selective (e.g., betaxolol) adrenergic blocking agents are also used in the treatment of open-angle glaucoma. The mechanism of action likely entails reduction of aqueous humor formation. Adverse ocular effects include ocular stinging and discomfort, tearing, itching and/or foreign body sensation, and ocular dryness. Systemic cardiovascular and pulmonary adverse effects are of greater concern, are not uncommon especially in predisposed individuals (e.g., the elderly, patients with underlying cardiovascular or respiratory system disease, or those taking xcex2-adrenergic blocking agents systemically for other conditions), and may occasionally be life-threatening.
In general, the above-mentioned agents can be used in combination therapy. For example, pilocarpine can be added to a timolol regimen to achieve further reduction in intraocular pressure. Similarly, an orally administered carbonic anhydrase inhibitor (e.g., acetazolamide) can be added to an ocular regimen to enhance treatment. Many adverse effects have been associated with the oral carbonic anhydrase inhibitors, including gastrointestinal, central nervous system, hematologic, renal, electrolyte (especially dangerous in patients with heart disease taking digitalis and other salt-wasting diuretics concurrently), and metabolic disturbances. Of course, the potential incidence of adverse effects increases when more than one agent is being used in a treatment regimen (See generally, McEvoy (ed.), AHFS Drug Information 93:1729-53 and 1767-79[1993]; and The Merck Manual of Diagnosis and Therapy, supra).
As set forth above, untreated glaucoma can result in severe consequences, including blindness. Clearly, new treatment methods and agents are needed and would be welcomed by those plagued by glaucoma who either cannot tolerate available treatment regimens or who are unwilling to undergo invasive surgical procedures.
The present invention describes chemical agents that can be used to treat glaucoma.
The compounds of the present invention cause a pharmacological perturbation of cellular contractility and perhaps secondarily, cell adhesions, mainly via disruption of the associated cytoskeletal structures or the modulation of their interactions with the membrane. Reduction in contractility and/or perturbation of these adhesions reduces the resistance of the trabecular meshwork to fluid flow and thereby reduces intraocular pressure in a therapeutically useful manner. However, an understanding of the mechanisms (e.g., the specific molecular mechanisms) is not necessary in order to utilize the present invention. Indeed, it is not intended that the present invention be limited to any particular mechanism(s).
The present invention contemplates methods of enhancing aqueous humor outflow in the eye of a subject to treat glaucoma, comprising: a) providing a subject with glaucoma; and b) administering to the subject an ophthalmic preparation comprising an effective amount of a non-comeotoxic serine-threonine kinase inhibitor, thereby enhancing aqueous humor outflow in the eye and treating the glaucoma. In one embodiment of the present invention, the serine-threonine kinase inhibitor is selected from the group consisting of H-7, ML-7, staurosporine, and KT-5926. In particular embodiments, the method of administration is topical. In other embodiments, the method of administration is intracameral. In still further embodiments, the method of administration is intracanalicular. In addition, the present invention provides compositions and methods suitable for the relaxation of actomysin (e.g., the potent contractile machinery consisting of actin and myosin filaments).
Moreover, the present invention contemplates a method of enhancing aqueous humor outflow in the eye of a subject to treat glaucoma, comprising: a) providing a subject with glaucoma; and b) administering to the subject an ophthalmic preparation comprising an effective amount of either H-7, staurosporine, or latrunculin-A, or a pharmaceutically acceptable salt thereof, thereby enhancing aqueous humor outflow in the eye and treating the glaucoma. In some embodiments, the method of administration is topical, whereas it is intracameral in other embodiments. In still further embodiments, the method of administration is intracanalicular.
In further embodiments, the present invention provides methods of enhancing aqueous humor outflow in the eye, comprising providing a subject and administering to said subject an ophthalmic preparation comprising an effective amount of a latrunculin B or a pharmaceutically acceptable salt thereof, thereby enhancing aqueous humor outflow in the eye and treating the glaucoma. In some preferred embodiments, the subject has glaucoma or is at risk for development of glaucoma. In alternative embodiments, the administration is topical, while in other embodiments the administration is intracameral, and still further embodiments the administration is intracanalicular. In some embodiments, the administration of latrunculin(s) (including but not limited to latrunculin-A) results in the binding of monomeric (G-) actin, which inhibits polymerization and leads to disruption of the actin networks.
The present invention provides effective and non-invasive methods of treating glaucoma without causing untoward and unacceptable adverse effects, such as corneal edema.
The present invention also provides methods of enhancing aqueous humor outflow in the eye of a subject, comprising: providing a subject, and administering an ophthalmic preparation comprising an effective amount of a non-corneotoxic cytoskeletal active agent that affects actin filaments to the subject, thereby enhancing aqueous humor outflow in the eye of the subject. In some preferred embodiments, the non-corneotoxic compound is a latrunculin. In some particularly preferred embodiments, the non-corneotoxic compound is selected from the group consisting of latrunculin-A and latrunculin-B. In other preferred embodiments, the non-corneotoxic compound is swinholide-A.
The present invention further provides methods of enhancing aqueous humor outflow in the eye of a subject, comprising: providing a subject and an effective amount of at least one non-corneotoxic ophthalmic preparation; and administering the non-corneotoxic ophthalmic preparation to the subject, wherein the preparation affects the actin filaments of the eye of the subject, and under conditions such that the aqueous humor outflow of the subject is enhanced. In preferred embodiments, the non-corneotoxic ophthalmic preparation comprises at least one macrolide. In particularly preferred embodiments, the macrolide is selected from the group consisting of latrunculin-A, latrunculin-B, swinholide-A, and jasplakinolide. In alternative embodiments, the subject has glaucoma. In still further embodiments, the administration is topical, while in other embodiments, the administration is intracameral, and in still further embodiments, the administration is intracanalicular.
The present invention also provides methods of enhancing aqueous humor outflow in the eye, comprising: providing a subject having glaucoma, and an ophthalmic preparation comprising an effective amount of at least one macrolide or a pharmaceutically acceptable salt thereof; and administering the ophthalmic preparation comprising an effective amount of a macrolide or a pharmaceutically acceptable salt thereof, to the subject thereby enhancing aqueous humor outflow in the eye of the subject, wherein the non-corneotoxic ophthalmic preparation affects the actin filaments of the eye of the subject. In particularly preferred embodiments, the macrolide is selected from the group consisting of latrunculin-A, latrunculin-B, swinholide-A, and jasplakinolide. In still further embodiments, the administration is topical, while in other embodiments, the administration is intracameral, and in still further embodiments, the administration is intracanalicular.
The present invention further provides methods for preventing the progression of glaucoma, comprising the steps of: providing a subject having glaucoma and a non-corneotoxic ophthalmic preparation that is capable of affecting actin filaments of an eye; and administering the non-corneotoxic ophthalmic preparation to the subject under conditions such that the progression of glaucoma is alleviated and/or prevented. In preferred embodiments, the non-corneotoxic ophthalmic preparation comprises at least one macrolide. In still further embodiments, the macrolide is selected from the group consisting of latrunculin-A, latrunculin-B, swinholide-A, and jasplakinolide. In still further embodiments, the administration is topical, while in other embodiments, the administration is intracameral, and in still further embodiments, the administration is intracanalicular.
Definitions
To facilitate understanding of the invention and the chemical schemes set forth in the disclosure that follows, a number of terms are defined below.
The term xe2x80x9cophthalmic preparationxe2x80x9d refers to a composition containing a compound active so as to forestall the progression of glaucoma as well as other pharmaceutically acceptable ingredients. The characteristics of the composition will depend on a number of factors, including the mode of administration. For example, the composition may be a solution, suspension or the like that can be administered topically as an eyedrop. In addition, the composition may be in a form suitable for intracameral administration; for example, microinjection through the cornea into the anterior chamber so that the compound can reach the trabecular meshwork. Alternatively, the drug could be administered intracanalicularly (e.g., by retrograde microinjection into the venous collector channels draining Schlemm""s canal or into Schlemm""s canal itself). This eliminates the risk of corneotoxicity. The ophthalmic preparation may contain diluents, adjuvants and excipients, among other things.
The term xe2x80x9ceffective amountxe2x80x9d refers to that amount of a preparation that is sufficient to produce the desired results. In particularly preferred embodiments, the term refers to that amount of an ophthalmic preparation that is required to successfully treat glaucoma. The effective amount of an ophthalmic preparation may depend on a number of factors, including the age, race, and sex of the subject and the severity of the glaucoma and other factors responsible for biologic variability. Though the term effective amount is not limited to a particular mechanism of action for a specific compound, an effective amount may be that amount of a compound able to disrupt cell junctions in the trabecular meshwork of the eye to increase aqueous humor outflow.
The term xe2x80x9csubjectxe2x80x9d includes humans as well as other animals, including but not limited to primates, rodents, canines, felines, etc. Indeed, it is not intended that the term be limited to any particular animal or type of animal.
The term xe2x80x9cglaucomaxe2x80x9d refers to an ophthalmologic disorder responsible for visual impairment. The disease is characterized by a progressive neuropathy caused at least in part by deleterious effects resulting from intraocular pressure on the optic nerve. The term glaucoma refers broadly to both primary glaucomas, which include open-angle, angle-closure, and congenital glaucomas, and secondary glaucomas, which occur as a sequel to ocular injury or preexisting disease. Though not limited to any particular type of glaucoma, it is anticipated that the pharmacological agents and compounds of the present invention will be most efficacious in the treatment of open-angle glaucoma. In addition, the term encompasses subclinical or pre-clinical stages of glaucoma, in which the patient does not or has not yet begun to experience visual impairment. Thus, it is intended that the term encompass any stage and/or form of glaucoma.
The term xe2x80x9cmanifestations of glaucomaxe2x80x9d refers to signs associated with glaucoma, including but not limited to loss of vision.
The term xe2x80x9caqueous humor outflowxe2x80x9d refers to the drainage of aqueous humor from the eye. As described in further detail below, aqueous humor leaves the eye by passive bulk flow via two pathways at the anterior chamber angle, the trabecular or conventional route and the uveoscleral, posterior, or unconventional route. The term aqueous humor outflow refers to drainage via both pathways.
As used herein, the term xe2x80x9cserine-threonine kinasesxe2x80x9d (or xe2x80x9cser-thr kinasesxe2x80x9d) refers to enzymes that phosphorylate serine and/or threonine residues of proteins. In particularly preferred embodiments, the term encompasses kinases that affect actinomysin contractility.
The terms xe2x80x9cserine-threonine kinase inhibitorsxe2x80x9d and xe2x80x9cser-thr inhibitorsxe2x80x9d refer to compounds known to be myosin light-chain kinase inhibitors. However, it is not intended that the term be limited to compounds that inhibit myosin light-chain kinase, as other targets are contemplated. These compounds primarily inhibit myosin light-chain kinase, thus inhibiting actomyosin-driven contractility; upon long exposure (xe2x89xa730 minutes), they cause deterioration of the entire microfilament system. These changes affect predominantly cell-extracellular matrix (C-ECM) adhesions. The ser-thr inhibitors include, but are not limited to, H-7, KT-5926, ML-7, and staurosporine.
As used herein, the term xe2x80x9ckinase inhibitorxe2x80x9d refers to compounds that block kinases. Thus, it is not intended that the present invention be limited to myosin light-chain kinase inhibitors, as it is contemplated that other kinase inhibitors will find use in the present invention, including but not limited to rho kinase inhibitors. In addition, this term encompasses compounds that block contractility and/or affect adhesions and other cytoskeletal functions.
The term xe2x80x9cnon-corneotoxicxe2x80x9d refers generally to the absence of medically-unacceptable side effects on the cornea. One of the primary side effects to be avoided is corneal edema, which is manifested by abnormal fluid accumulation within the intercellular spaces of the cornea. A main etiology of corneal edema is impairment of the corneal endothelium due to the introduction of drugs and other chemical compounds. Specular microscopy can be used to evaluate drug effects on the corneal endothelium, and the absence of a statistical change in corneal endothelial cell counts is indicative of a non-comeotoxic compound. In addition, the presence of corneal toxicity can be evaluated through ocular examination, which may include slit lamp biomicroscopy, gonioscopy, and corneal thickness measures.
The term xe2x80x9ccytoskeletal active agentxe2x80x9d refers broadly to compounds that affect the complex network of cytoplasmic filaments known collectively as the cytoskeleton. The three major classes of cytoskeletal filaments are actin microfilaments, intermediate filaments and microtubules. Generally speaking, cytoskeletal active agents work by perturbing the cytoskeletal filaments, through promotion of disruption of the filaments, interference with their stability, or disturbance of their interaction with other cytoskeletal components, and, indirectly, with the extracellular matrix.
The term xe2x80x9ccell junctionsxe2x80x9d refers to cell-to-cell (Cxe2x80x94C) interactions/adhesions and to cell-to-extracellular matrix (C-ECM) interactions/adhesions (i.e., Cxe2x80x94C adhesions and cell-extracellular matrix [C-ECM] adhesions), both of which are necessary for integrated cellular activity and tissue architecture. Cell adhesion is closely associated with the actin microfilaments, which interact with both C-ECM and Cxe2x80x94C junctions through a complex submembrane interlinking xe2x80x9cplaque.xe2x80x9d Compounds which disrupt cell junctions may do so by affecting the junction directly or by disrupting the actin network or promoting its dissociation from the membrane-bound plaque. More specifically, compounds which interfere with the formation of the actin microfilaments, promote disruption of the filaments, interfere with actin assembly into bundles, or disturb the relationship between actin and myosin or the plaque will disrupt cell junctions and cause cells to pull apart from each other or from the extracellular matrix.
The compounds of the present invention encompass pharmacological agents that directly affect the trabecular meshwork of the eye and/or Schlemm""s canal. The trabecular meshwork, a complex tissue consisting of specialized endothelial cells, connective tissue beams, and extracellular matrix, is responsible for the resistance to aqueous humor outflow. The compounds of the present invention affect, among other things, Cxe2x80x94C and C-ECM adhesions in the trabecular meshwork.